The overall objective of this program is to elucidate the molecular and genetic basis for abnormalities in lipoprotein metabolism that predispose to premature artery disease. The identification and characterization of such pathophysiological changes in humans will permit more rational management and better design of appropriate therapy in order to delay the onset of premature coronary artery disease. We will address this goal with four studies relating to abnormalities of high density lipoprotein (HDL). One project will focus on mapping of atherogenic traits, including LDL density, HDL level, and apolipoprotein B level in familial combined hyperlipidemia, the most common condition associated with premature therosclerosis. Mapping, followed by identification of previously undetected genes for these traits, will advance both the basic biology of lipid disorders and the potential to diagnose, prevent, and treat vascular disease. The other three projects will focus on proteins that are central to HDL metabolism: apolipoprotein (apo) A-L, phospholipids transfer protein (PLTP), and serum amyloid A (SAA). One part of the apo A-l project will focus on oxidative modifications that affect HDL's ability to remove cholesterol by the ABCA 1 pathway, a key early event in reverse cholesterol transport. Another part will identify the pathways for apo A-l reflect oxidative .in the artery wall and determine whether plasma levels of oxidized apo A-l reflect oxidative stress and inflammation. The PLTP project will uncover thebiochemical basis and functional differences of the different forms of PLTP and will identify the structural domains of PLTP and ABCA 1 that are critical for the interaction of PLTP with ABCA1 and for facilitation of lipid efflux from cells through this pathway. The study of serum amyloid A (SAA), which is carried on HDL, will explore the link between atherosclerosis and inflammation and SAA's role in HDL retention and atherosclerosis. By identifying genetic changes that lead to FCHL and alter HDL, studying proteins involved in reverse cholesterol transport (apo A-l and PLTP), and investigating the relationship between HDL and inflammation, this program project will take a multifaceted approach to elucidating the roles of HDL and related proteins in premature coronary artery disease.